Main Gadolinium(III)-based contrast probes have been widely used in clinical MRI. So far, there are at least nine formulations of Gd-containing contrast agents approved for human use in the U.S., and they are assisting more than 10 million magnetic resonance imaging (MRI) scans per year. Free Gd is known to have a high toxicity profile, hence clinically used Gadolinium agents are all in the form of Gd-chelator complexes. Despite the complexation, however, these contrast agents are found to cause severe nephrogenic systemic fibrosis (NSF), especially for patients with renal diseases or poor renal functions (Perazella, Curr. Drug Safety 2008, 3(1):67-75; Chrysochou et al., Clin. J. Am. Soc. Neph. 2010, 5(3): 484-489; Perazella et al., Clin. J. Am. Soc. Neph. 2007, 2(2):200-202). For this reason, the FDA has issued warnings on the use of several Gd-based contrast agents in patients with kidney dysfunction (Thomsen et al., Clin. Rad. 2006, 61(11):905-906; Thomsen, Eur. Rad. 2006, 16(12):2619-2621; Hellman, Sem. Neph. 2011, 31(3):310-316.5-7). This status underscores the significance of developing alternative contrast agents with more favorable safety profiles.
One approach that has been investigated is to load or imbed Gd(III) into a nanoparticle capsule/carrier that can suppress the Gd release while maintaining the T1-shortening capacity. Examples of this approach include Gd2O3 nanoparticles (Bridot et al., J. Am. Chem. Soc. 2007, 129(16):5076-5084), Gd-loaded silica nanoparticles (Vivero-Escoto et al., Small 2013, 9(20):3523-3531), and Gd-doped Fe3O4 nanoparticles (Zhou et al., Adv. Mater. 2012, 24(46):6223-6228). Due to their relatively large sizes, however, these nanoparticles are mostly accumulated in the reticuloendothelial (RES) organs after injection, most prominently the liver. Subsequent particle degradation may cause slow release of Gd(III) to the surroundings, and the long-term impact is largely unknown. Thus, what are needed are new Gd-based contrast agents that have improved safety profiles. The compositions and methods disclosed herein address these and other needs.